The cardiovascular properties of serotonin (5-HT) have been known for some time—its name reflects its presence in serum and its action in increasing vascular tone. Serotonergic medications are routinely used to treat depressive and anxiety disorders, and the association of depression with cardiovascular disease has become well established.2 Recent studies have confirmed the colloquial wisdom that anxiety (especially panic) and hypertension are linked.

In this article, we examine the trinity of serotonin—serotonergic dysfunction, autonomic panic, and normal-weight essential hypertension— and the evidence that hypertensive individuals who experience panic with autonomic symptoms may be a group of patients in whom serotonergic dysfunction plays a key role. We discuss implications of this model, including the potential utility of SSRIs as antihypertensives in this cohort.

The role of serotoninSSRIs are well established as first-line treatments of clinical anxiety disorders.3 Their wide availability, relative safety in overdose, limited ad­verse effects, and broad clinical effectiveness have contributed to their popularity. Indeed, their categorization as antidepressants seems increasingly inadequate because these agents have been found to be clinically useful in a range of psychiatric conditions.

In recent years, there has been much concern about emergent suicidality in adults and children treated with SSRIs. Such fears appear to have eroded clinical confidence in these medications, despite some methodological concerns.4-6 Sadly, a parallel decrease in prescribing of SSRIs appears to be associated with increased suicide rates—a powerful reminder of the need to closely monitor all patients for whom these powerful medicines are prescribed and the complex implications of health policy modification.7 Most authorities continue to advocate considered use of SSRIs and/or cognitive-behavioral therapy (CBT) in clinical anxiety states, although the evidence base supporting combination therapy over SSRIs alone is surprisingly sparse.8

Patients are commonly told that SSRIs work by “correcting” an abnormality in the 5-HT system, but only recently has evidence emerged to support this correlation with anxiety. One difficulty has been competing theories that patients with anxiety disorders have either too little or too much 5-HT in the synaptic cleft.9

The 5-HT deficit model proposes that 5-HT reuptake blockade leads to increased availability of 5-HT, which, in turn, rapidly leads to a decreased rate of firing of the raphe nucleus. The initial net result is little overall change in cortical 5-HT concentration. After a few weeks to months, however, the raphe firing rate recovers, and eventually 5-HT cerebral concentration reaches levels that are therapeutic. This model accounts for the delayed onset of antidepressant and anxiolytic action as well the initial transient increase in anticipatory anxiety.

An alternative (5-HT excess) model proposes that increased levels of 5-HT produce an increase in anticipatory anxiety initially; however, a gradual down-regulation of supersensitive postsynaptic receptors (or a decrease in presynaptic excitability) produces an anxiolytic effect.